MicroRNAs (miRNAs) are single-stranded RNAs (ssRNA) of 19-25 nucleotides in length that function as guide molecules in post-transcriptional gene silencing, by base pairing with target mRNAs. Since one miRNA can regulate expressions of multiple genes and about 1/3 of the human genes are regulated by miRNAs, variants in miRNAs have intriguing potential roles in the psychiatric diseases. To date there has been little study of genomic variation in miRNA genes, or the relationships between miRNA variants and psychiatric disorders, or where miRNA variants are correlated with variations in gene expressions in the brain. To promote such knowledge, we propose to use deep resequencing to exhaustively identify variants in all known human miRNAs. Then we will study the correlation between miRNA variants and gene expression in brain, and association of miRNA variants with schizophrenia (SZ) and bipolar disorder (BD). We will resequence all 462 known human miRNA genomic DNA sequences in 310 Caucasian individuals including BD, SZ, and normal controls (CN). 210 of the 310 individuals have already had microarray study of gene expression in brain or lymphoblastoid cells. Resequencing will identify all common and many rare variants. We will then test association of disease with genotypes of these variants in a large collection of case-control BD and SZ samples from the NIMH Genetics Initiative, including 3000 BD, 3000 SZ and 2250 CN. We will also test for correlations between sequence variants in miRNAs and gene expression data (as quantitative traits) in Stanley brain samples and CEPH lymphoblastoid cell samples. We will use appropriate statistical methods to approach multiple testing and potential population stratification problems. These findings will potentially enhance our understanding of the miRNA genes and their potential roles in etiology of BD and SZ. Development of new diagnoses and treatments may result.